Several members of a family of human T-lymphotropic retroviruses (HTLV) have been isolated by researchers and are strongly associated with a variety of human disease conditions. Known in the art as the HTLV family of T4 tropic retroviruses, these retroviruses are known to cause T-cell proliferation leukemia, T-cell depletion, and immunosuppression in infected humans. Subgroup Q HTLV-I is the putative pathogen in T-cell proliferation and leukemia. Subgroup HTLV-II induces T-cell proliferation in vitro but its role in disease is currently unclear. Subgroup HTLV-III has recently been identified as the putative causal agent of AIDS and is strongly associated with ARC and Pre-AIDS conditions.
More specifically, HTLV-I was isolated from a black American with an aggressive form of T-cell lymphoma and has been etiologically linked to the pathegenesis of adult T-cell leukemia/lymphoma (ATLL) and acute lymphocytic leukemia (ALL). In vitro infection with HTLV-I has been shown to alter T-cell function and, in some instances, leads to T-cell death. HTLV-II has been isolated from a patient with a T-cell variety of hairy cell leukemia. HTLV-III has been isolated from AIDS patients and pre-AIDS patients suffering from chronic generalized lymphadenopathy. Both HTLV-I and HTLV-II also have been isolated from patients with AIDS.
It should be noted that HTLV-III is also referred to as LAV. This is because the Institute Pasteur in Paris reported the isolation of a retrovirus from a patient with AIDS related symptoms and named it lymphadenopathy-associated virus (LAV). At essentially the same time Dr. Robert Gallo of the National Institute of Health, in Bethesda, Maryland, reported similar success in isolating a retrovirus from patients with or at risk from AIDS and named it HTLV-III. A later detailed analysis of the genetic structures of the two viral isolates showed them to be virtually identical.
Like all retroviruses, members of the HTLV family are viruses whose genetic material is composed of ribonucleic acid which is later transcribed into DNA by reverse transcriptase and becomes permanently incorporated into the DNA of the host's genetic material. Thereafter, the retrovirus reproduces itself by transcribing its DNA into RNA which directs the synthesis of the components of new infectious viral particles which bud out of the infected cells and initiate new cycles of infection, integration and rapid viral multiplication. Once retroviral integration into the host genetic material occurs it precludes the elimination of the viral blueprints through therapeutic means.
Cures and effective vaccination agents are presently unknown. Current treatments generally involve suppression of viral multiplication through antiviral drugs in the hope of protecting uninfected cells. Efforts are currently being directed to the development of effective vaccines which can be administered to an entire population in the hope of effectively controlling the spread of infection.
Of all the diseases engendered by HTLV subgroups, AIDS, pre-AIDS and ARC are receiving the most attention. Though AIDS is a relatively recently recognized disease, it has turned up in practically every European country as well as Africa, the Caribbean, and the United States. In spite of the fact that The Centers for Disease Control (CDC) define AIDS narrowly as an acquired immune deficiency associated with one or more of only four life-threatening opportunistic infections or Kaposi's Sarcoma, at least 12,000 cases of CDC-defined AIDS were reported by mid-1985. Moreover, both the CDC and National Institutes of Health (NIH) predict that there will be approximately 40,000 AIDS cases reported nationwide by the end of 1986. Cures and effective vaccinations are not yet in sight but are being actively explored in many laboratories. At present, the prognosis is uniformly bleak. AIDS is transmissible, always fatal, and medically uncontrollable. The current mortality rate of the disease is 50% and, up to the present, no one has been known to recover from this apparently irreversible pathological process. Officials of the NIH estimate that approximately 1,000,000 persons, nationwide, are already infected with the disease which, due to its long period of latency has yet to outwardly manifest itself as AIDS or AIDS-related diseases.
The primary targets of HTLV-III affliction in the human body are specific subpopulations of T-cells, certain lymphocytes or white blood cells called T4 lymphocytes which are "helper" and regulatory cells essential to proper immune response. In vitro, HTLV-III preferentially multiplies in and kills human T4 lymphocytes. In vivo, infected individuals exhibit an unusually low portion of T4 lymphocytes resulting in severe immune deficiency and the associated opportunistic infections and rare forms of cancer. These infections include unusual forms of pneumonia due to protozoan parasites (pneumocystis carinii pneumonia or PCP), thrush (a fungus infection), Burkitt's lymphoma, and Kaposi's sarcoma.
Though the CDC defined AIDS narrowly in order to ensure accurate reporting for public health surveillance purposes, it was clear from the outset that the CDC reported cases of only the more advanced stages of AIDS and that a much larger population of infected individuals with a broad range of symptoms could be observed. These symptoms range from minor non-specific symptoms and detectible HTLV-III antibodies to persistent lymphadenopathy (enlargement of lymph nodes) accompanied or not by more serious symptoms (ARC) to markedly deficient cell mediated immunity associated with infections (opportunistic or not) other than those included in the CDC definition, and other types of cancers such as lymphoma. An estimated 50,000 to 100,000 Americans show early signs of ARC which include swollen lymph glands, fatigue, malaise, fever, night sweats, diarrhea, and gradual loss of weight. Additionally, because HTLV-III also invades brain cells, a considerable number of infected individuals suffer from mental and neurological problems ranging from forgetfulness and speech impairment to tremors, seizures, and dementia.
Considerable effort is being devoted to the development of effective treatments for AIDS and pre-AIDS conditions. Laboratory screening of over 100 potential compounds has been carried out and several compounds are currently being tried on patients. These include HPA-23, Ribaviran, and Suramin. Though treatment with these compounds has produced promising results including decreased viral activity and enhanced immune function, none of these agents is close to being declared an agent that will suppress the virus with minimal toxicity for any length of time. For example, HPA-23, a tungsten-antimony derivative, has serious toxicity problems including platelet-count depression. Similarly, Suramin may cause fever and abnormal renal function. The major drawback to Ribaviran is the developmont of anemia. As a result, patients are placed on two and three week courses of treatment which, hopefully, can be repeated after adverse effects have subsided.
It is a wide spread belief among practitioners in the field that no single therapeutic agent will provide a full answer to controlling AIDS. Rather, investigators suspect effective treatment will involve administration of multiple compounds, at least one compound to eliminate the presence of the virus and additional compounds to restore immune function.
The recent emphasis on AIDS research has produced quantitative data evidencing the staggering social and personal costs of this disease. The CDC recently reported that, based upon its analysis of the 10,000 AIDS cases reported in the United States by mid-1985, the average medical costs alone, from time of diagnosis to death, are $147,000, making AIDS the most expensive infectious disease. Moreover, because the majority of AIDS patients are relatively young, the total expense to the nation including lost work is estimated by the CDC to be on the order of $5 to $6 billion. When these estimates are taken in conjunction with the fact that the CDC expects a doubling of the number of reported AIDS cases every nine months, the pressing need for resolution of the AIDS epidemic becomes manifest. Factoring in the additional personal and social costs for diseases engendered by or associated with other members of the HTLV family, further emphasizes the pressing need for a resolution of these disease conditions.
As discussed above, in addition to AIDS, retroviruses of the HTLV family are known to be responsible for at least one type of T-cell leukemia in humans and are strongly associated with other forms of the disease. Leukemia is a progressive, malignant disease of the blood forming organs marked by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. It is accompanied by a reduced number of erythrocytes and blood platelets which results in anemia and increased susceptability to infection and hemorrhage. Typical symptoms of leukemia include fever, pain in the joints and bones and swelling of the lymph nodes, spleen and liver. Types of leukemia are classified clinically on the basis of the duration and character of the disease (acute or chronic) the type of cell involved (myelocytic, lymphoid, or monocytic), and the increase or nonincrease in the number of abnormal cells in the blood (leukemic or aleukemic).
In acute leukemia the white cells resemble precursor or immature cells and are larger than normal. The immature cells are incapable of performing their normal immunological function. In contrast to acute leukemia, in chronic leukemia the white cells are more mature and have a limited capacity to oppose invading organisms. Additionally, white cells do not accumulate as rapidly as they do in acute leukemia.
The different types of leukemia are predominate in different age groups. For example, acute lymphocytic leukemia (ALL) occurs in young children while acute myelocytic leukemia occurs primarily in young adults. Chronic lymphoid leukemia is found primarily in persons from 50 to 70 years of age and chronic myelocytic leukemia occurs in persons between 30 to 50 years of age.
In addition to the clinical evidence for the viral etiology of various forms of leukemia, it is also known that heredity plays a role in some forms of the disease. For example, leukemia frequency is fifteen times higher among those with Down's syndrome as opposed to the population in general. Similarly, the possibility of leukemia is noticably greater in persons having identical twins with the disease.
Until recently, the evidence for a viral etiology of human leukemia was circumstantial and consisted of the finding of retrovirus-type viral particles in human leukemic tissue and the demonstration of reverse transcriptase and 70S high molecular weight RNA in human leukemia cells. The most convincing evidence for viral etiology comes from the study of adult T-cell leukemia-lymphoma (ATLL) endemic to southwestern Japan and identified in the Caribbean and southeastern United States and the recent, consistent isolation of HTLV-I from ATLL patients. This convincing evidence came from the work of Dr. Robert Gallo who, in 1978, identified a unique retrovirus in patients with mature T-cell malignancies which was shown to be a unique, exogenously acquired retrovirus far removed from any then known animal retrovirus in terms of antigenicity, amino acid sequence, and nucleic acid sequence homology. It was subsequently realized that these patients suffered from a disease identical to ATLL as described in Japan.
HTLV-I has been etiologically linked to the pathogenesis of ATLL and is known to cause T-cell proliferation in leukemia. Similarly, HTLV-II was isolated from a patient with a T-cell variant of hairy cell leukemia and is known to induce T-cell proliferation in vitro; however, its role in the disease is currently unclear. Nonetheless, it is strongly implicated in the development of human leukemia.
Currently, as with AIDS, there is no known treatment existing that can permanently cure or control leukemia. Therapeutic measures for the management of the disease are chosen according to individual patient need and include radiation therapy, corticosteroid therapy, chemotherapy using antineoplastic agents, blood platelet and granulocyte transfusions, and antibiotics. The goals of the treatment are to rid the blood, bone marrow, and tissues of leukemic cells and to control or prevent the proliferation of malignant cells. In some cases, immunotherapy and the transplanting of bone marrow from another person may be utilized for treatment. Transfusion and replacement of blood cells may relieve the symptoms of leukemia and the antineoplastic agents temporarily destroy the leukemic cells thereby prolonging the life of the afflicted patient. Remissions are known to last as long as fifteen years or more.
Though limited cross-reactivities are present between the known subgroups of the HTLV family of T4 tropic retroviruses, Western Blotting techniques with ligates of HTLV-I, HTLV-II, and HTLV-III show that the three subgroups share distinct antigenic cross-reactivity with respect to the major envelope gene product, thereby confirming the that the three known subgroups of this family of retroviruses are immunologically related.